Declomycin

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Declomycin

CLINICAL PHARMACOLOGY

Pharmacokinetics

The absorption of demeclocycline
is slower than that of tetracycline. The time to reach the peak concentration
is about 4 hours. After a 150 mg oral dose of demeclocycline tablet, the mean
concentrations at 1 hour and 3 hours are 0.46 and 1.22 μg/mL (n=6) respectively.
The serum half-life ranges between 10 and 16 hours. When demeclocycline
hydrochloride is given concomitantly with some dairy products, or antacids
containing aluminum, calcium, or magnesium, the extent of absorption is reduced
by more than 50%. Demeclocycline hydrochloride penetrates well into various
body fluids and tissues. The percent of demeclocycline hydrochloride bound to
plasma protein is about 40% using a dialysis equilibrium method and 90% using
an ultra-filtration method. Demeclocycline hydrochloride, like other
tetracyclines, is concentrated in the liver and excreted into the bile where it
is found in much higher concentrations than in the blood. The rate of
demeclocycline hydrochloride renal clearance (35 mL/min/1.73 m²) is
less than half that of tetracycline. Following a single 150 mg dose of
demeclocycline hydrochloride in normal volunteers, 44% (n=8) was excreted in
urine and 13% and 46%, respectively, were excreted in feces in two patients
within 96 hours as active drug.

Microbiology

Mechanism of Action

The tetracyclines are primarily bacteriostatic and are
thought to exert their antimicrobial effect by the inhibition of protein
synthesis. The tetracyclines, including demeclocycline have a similar
antimicrobial spectrum of activity against a wide range of gram-negative and
gram-positive organisms.

Mechanism(s) of Resistance

Resistance to tetracyclines may be mediated by efflux,
alteration in the target site of tetracycline, enzymatic inactivation, and
decreased bacterial permeability to the tetracycline or a combination of these
mechanisms.

Cross Resistance

Cross-resistance between antibiotics of the tetracycline
family occurs.

Demeclocycline has been shown to be active against most
isolates of the following bacteria, in vitro and/or in clinical infections as
described in the INDICATIONS AND USAGE section.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should
provide the results of in vitro susceptibility test results for antimicrobial
drug products used in resident hospitals to the physician as periodic reports
that describe the susceptibility profile of nosocomial and community-acquired
pathogens. These reports should aid the physician in selecting an antibacterial
drug product for treatment.

Dilution Techniques

Quantitaive methods are used to determine antimicrobial
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
susceptibility of bacteria to antimicrobial compounds. The MICs should be
determined using a standardized test method (broth and/or agar)1,2,3.
The MIC values should be interpreted according to the criteria in Table 1.

Diffusion techniques

Quantitative methods that require measurement of zone
diameters can also provide reproducible estimates of the susceptibility of
bacteria to antimicrobial compounds. The zone size provides an estimate of the
susceptibility of bacteria to antimicrobial compounds. The zone size should be
determined using a standardized test method.2,4 This procedure uses
paper disks impregnated with 30 mcg tetracycline to test the susceptibility of
microorganisms to tetracycline. The disc diffusion interpretive criteria are
provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for
Tetracycline

Pathogen

Minimum Inhibitory Concentration (mcg/mL)

Disk Diffusion (zone diameters in mm)

S

I

R

S

I

R

Enterobacteriaceae, Acinetobacter spp.

≤ 4

8

> 16

≥ 15

12 -14

< 11

Haemophilus influenzae

< 2

4

> 8

> 29

26-28

< 25

Neisseria gonorrhoeae

< 0.25

0.5-1

> 2

> 38

31-37

< 30

Staphylococcus aureus

≤ 4

8

≥ 16

≥ 19

15-18

≤ 14

S. pneumoniae (non-meningitis isolates)

≤ 1

2

≥ 4

≥ 28

25-27

≤ 24

Bacillus anthracis

< 1

--

--

--

--

--

Franciscella tularensis

< 4

--

--

--

--

--

A report of Susceptible indicates
that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial
compound reaches the concentrations at the infection site necessary to inhibit
growth of the pathogen. A report of Intermediate indicates that the result
should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be
repeated. This category implies possible clinical applicability in body sites
where the drug product is physiologically concentrated or in situations where a
high dosage of the drug product can be used. This category also provides a
buffer zone that prevents small uncontrolled technical factors from causing
major discrepancies in interpretation. A report of Resistant indicates that the
antimicrobial is not likely to inhibit growth of the pathogen if the
antimicrobial compound reaches the concentrations usually achievable at the
infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test
procedures require the use of laboratory controls to monitor and ensure the
accuracy and precision of supplies and reagents used in the assay, and the
techniques of the individuals performing the test.1,2,3,4 Standard
tetracycline powder should provide the following range of MIC values noted in
Table 2. For the diffusion technique using the 30 mcg tetracycline disk, the
criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for
Tetracycline

QC Strain

Minimum Inhibitory Concentrations (mcg/mL)

Disk Diffusion (zone diameters in mm)

Escherichia coli ATCC* 25922

0.5 to 2

18 -25

Staphylococcus aureus ATCC 29213

0.12 to 1

----

Staphylococcus aureus ATCC 25923

----

24-30

Haemophilus influenzae ATCC 49247

4 to 32

14 -22

Neisseria gonorrhoeae ATCC 49226

0.25 - 1

30 - 42

Streptococcus pneumoniae ATCC 49619

0.06 - 0.5

27 - 31

*ATCC = American Type Culture Collection

Animal Pharmacology And Animal Toxicology

Hyperpigmentation of the thyroid has been produced by
members of the tetracycline class in the following species: in rats by
oxytetracycline, doxycycline, tetracycline PO4 and methacycline; in minipigs by
doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by
doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO4, methacycline, doxycycline,
tetracycline base oxytetracycline HCl, and tetracycline HCl, were goitrogenic
in rats fed a low iodine diet. This goitrogenic effect was accompanied by high
radioactive iodine uptake. Administration of minocycline also produced a large
goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs
has also resulted in the induction of thyroid hyperplasia in the following: in
rats and dogs (minocycline), in chickens (chlortetracycline) and in rats and
mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats
and rats treated with oxytetracycline.